| The trifluoromethyl group enjoys a privileged role in the realm of medicinal chemistry. Its incorporation into drug molecules often enhances efficacy by (i) promoting electrostatic interactions with targets, ( ii) improving cellular membrane permeability, and (iii) increasing the metabolic robustness of a drug. For these reasons, common pharmacophores often include trifluoromethyl groups, either adjacent to alcohols or within aryl ring systems. However, this structural bias for CF3 incorporation into drugs is more likely an outcome of synthetic limitations rather than inherent biological activity of these specific motifs. This thesis describes the development of novel trifluoromethylation reactions via photoredox catalysis to access unique types of alkyl, aryl, and heteroaryl CF3 architectures.;Photoredox catalysis is a mode of reactivity recently introduced by our laboratory that provides a mild and efficient method for accessing electrophilic radicals such as ·CF3. This photosynthesis-inspired strategy relies on the excitation of highly tunable photocatalysts with a household light bulb to provide a strongly oxidizing and reducing catalyst for the generation of high-energy, reactive species. The successful merger of this technology with organocatalysis---or the use of small organic molecules for the direct functionalization of carbonyl-containing molecules---enabled the development of the first enantioselective alpha-trifluoromethylation of aldehydes. This dual catalytic approach allows for the controlled formation of two reactive intermediates, which selectively and efficiently react with one another to generate a wide range of novel alpha-fluoroalkyl carbonyls.;We further established photoredox catalysis as a valuable strategy for CF3 incorporation in the direct C--H trifluoromethylation of unactivated heteroarenes and arenes. Making use of this approach for mild radical generation, we found that a broad range of aromatic systems is amenable to direct functionalization by electrophilic radicals. Many of the molecules that we synthesized using this protocol would be otherwise difficult to access by standard cross coupling technology. The value of this new strategy for CF3 incorporation into late-stage synthetic intermediates, especially to the field of drug development, is demonstrated through examples of the direct trifluoromethylation of several widely prescribed medicinal agents. |
